Conversion of cholesterol to bile acids in the liver is initiated by the rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1) and excretion of bile acids from the liver is mediated by the bile salt export pump (BSEP). The expression of CYP7A1 and BSEP is coordinately regulated by a negative feedback and positive feed-forward mechanism, respectively, through bile acid-mediated activation...

The bile salt export pump (BSEP, ABCB11) is predominantly responsible for the efflux of bile salts, and disruption of BSEP function is often associated with altered hepatic homeostasis of bile acids and cholestatic liver injury. Accumulating evidence suggests that many drugs can cause cholestasis through interaction with hepatic transporters. To date, a relatively strong association between dru...

Bile acid accumulation in hepatocytes due to inhibition of the canalicular bile salt export pump (BSEP/ABCB11) has been proposed as a mechanism for bosentan-induced hepatotoxicity. The observation that bosentan does not induce hepatotoxicity in rats, although bosentan has been reported to inhibit rat Bsep and cause elevated serum bile acids, challenges this mechanism. The lack of hepatotoxicity...

The efflux transporter responsible for the canalicular elimination of bile salts from the hepatocytes is the bile salt export pump (BSEP, ABCB11). Absence or inhibition of this transporter leads to bile salt retention in the hepatocyte and in turn can lead to cholestatic liver disease. We expressed the BSEP/Bsep protein from three species (human, rat, and mouse) in a baculovirus-infected Sf9 sy...

Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of...

A comprehensive analysis was performed to investigate how inhibition of the human bile salt export pump (BSEP/ABCB11) relates to clinically observed drug-induced liver injury (DILI). Inhibition of taurocholate (TA) transport was investigated in BSEP membrane vesicles for a data set of 250 compounds, and 86 BSEP inhibitors were identified. Structure-activity modeling identified BSEP inhibition t...